Diltiazem treatment for pre-Clinical hypertrophic cardiomyopathy sarcomereMutation carriers: A pilot randomized trial to modify disease expression

Objectives: The study sought to assess the safety, feasibility, and effect of diltiazem as disease-modifying therapy forat-risk hypertrophic cardiomyopathy (HCM) mutation carriers. Background: HCM is caused by sarcomere mutations and characterized by left ventricular hypertrophy (LVH) with increased risk of heart failure and sudden death. HCM typically cannot be diagnosed early in life, although subtle phenotypes are present. Animal studies indicate that intracellular calcium handling is altered before LVH develops. Furthermore, early treatment with diltiazem appeared to attenuate disease emergence. Methods: In a pilot, double-blind trial, we randomly assigned 38 sarcomere mutation carriers without LVH (mean 15.8 years of age) to therapy with diltiazem 360 mg/day (or 5 mg/kg/day) or placebo. Treatment duration ranged from 12 to 42 months (median 25 months). Study procedures included electrocardiography, echocardiography, cardiac magnetic resonance imaging, and serum biomarker measurement. Results: Diltiazem was not associated with serious adverse events. Heart rate and blood pressure did not differ significantly between groups. However, mean left ventricular (LV) end-diastolic diameter improved toward normal in thediltiazem group but decreased further in controls (change in z-scores,+0.6 vs. -0.5; p< 0.001). Mean LV thickness-to-dimension ratio was stable in the diltiazem group but increased in controls (-0.02 vs.+0.15; p= 0.04). Among MYBPC3 mutation carriers, LV wall thickness and mass, diastolic filling, and cardiac troponin I levels improved in thosetaking diltiazem compared with controls. Four participants developed overt HCM, 2 in each treatment group. Conclusions: Pre-clinical administration of diltiazem is safe and may improve early LV remodeling in HCM. This novelstrategy merits further exploration. (Treatment of Preclinical Hypertrophic Cardiomyopathy With Diltiazem; NCT00319982).